Metabolic and enzymatic systems of organisms have evolved to incorporate phenolics, phenolic acids, and flavonoids, readily available in the environment from plant food sources, into the associated biochemical pathways of every major metabolic system. Not only do flavonoids have a physiological impact on a multitude of metabolic systems, but they are inherently part of the normal operation of such systems. As part of natural evolution, a flavonoid binding site has been conserved and distributed universally across these pathways. When a chemical reaction is overloaded with reagents, such as excessive glucose, or if there is an impairment of a metabolic component, such as a deformity of a protein, intermediate metabolites build to a concentration which can lead to the dysfunction of the pathway or associated pathways and the expression of a disease condition. A major role of flavonoids is to down and or up regulate certain enzymes to reduce the accumulation of these intermediates, ameliorating their negative effect on the organism.
Because of the distribution of a flavonoid binding site across several pathways, flavonoids have a regulatory impact on several enzymes in systems associated with disease conditions. Most other therapeutics for a disease condition target one to two target enzymes associated with a disease, while the flavonoid targets several.
Disease Classes
There are sixty-four (64) key enzymes distributed across six (6) disease categories. Most drugs used to treat these diseases either down-regulate or up-regulate a target enzyme associated with these diseases.
A listing of each major disease category and the target enzymes associated with such diseases follows.
Cancer
TARGET ENZYMES: Inositol 1,4,5 Triphosphate Kinase (IP3K), Protein Kinase CK2, DNA Topoisomerase II, Mitogen Activated Protein Kinase, CYP 181, Kinase 1 (MEK), MAPK Kinase 4 (MKK4), Glycoxalase, CYP 1A1, Cyclooxygenase, Thioredoxin Reductase, Nuclear Factor Kappa B (NF-Kappa B), Tyrosine Kinase (MET), Extracellular Signal Regulated Kinase (ERK 1-2), HSP 70 ATPase, Xanthine Oxidase, Phostphatidylinositol-3, RAF Kinase, Matrix Metallo Proteinase 1-18, MRP-1, Urokinase, 3-Phosphoglycerate Kinase, Aromatase (CYP-19), X Protein Kinase (XK), Ornithine Decarboxylase (ODC), and Inositol Polyphosphate Multi Kinase (IPMK).
Diabetes and Metabolic Syndrome (Diabetes Mellitus Type 1, Diabetes Mellitus Type 2, Gestational Diabetes, Metabolic Syndrome, Obesity, Glycogen Storage Disorder)
TARGET ENZYMES: Pyruvate Carboxylase, Fatty Acid Synthase, Alpha Amylase, Mitogen Activated Protein Kinase, MAP K (4), Cholesterol Acyl Transferase, Liver Xanthine Oxidase, Glucokinase, Extracellular Regulated Enzyme (ERK), Aldose Reductase, Lipase, Acetyl Co A, Kinase (1), Glucosidase, Angiotensin Converting Enzyme (ACE), 12-Lipo-oxygenase, and HMG-CoA, Kinase (MEK).
Cardiovascular Disease (Hypercholesterolemia, Ischemia, Hypertension, Endocarditis, Myocarditis, Cerebrovascular Disorder, Vascular Permeability, Ischemia)
TARGET ENZYMES: Aceto Acetyl CoA, Squalene Synthase, Oxidosqualene Cyclase, Angiotensin Converting Enzyme, Acetyl CoA, HMG CoA reductase, HMG CoA, and Cholesterol Transferase.
Inflammation and Pain (Acute Pain Disorder, Migraine, Headache, Arthritis, Psoriasis, Asthma, Alcohol Toxicity, Crohn's Disease, Inflammatory Bowel Syndrome, Colitis, Irritated Bowel Syndrome, Rosacea)
TARGET ENZYMES: Glyoxalase 1, Glyoxalase 2, Kinase (1), Polymerase (PARP-1), Mitogen Activated Protein Kinase (MAP K), Nuclear Enzyme Polymerase (ADP Ribose), Caspase 8, MAP K (4), MKK4, Elastase, COX 1, and COX 2.
Neurological Diseases (Alzheimer's Disease, Huntington's Disease, Schizophrenia, Traumatic Brain Injury, Parkinson's)
TARGET ENZYMES: Tyrosine Kinase, Alpha Secretase, Caspase 3, Protease, Beta Site APP Cleaving Enzyme 1 (BACE-1), Kinase (PLK2), Tau Protein Kinase, Beta Secretase, Gamma Secretase, Intercellular Adhesion Molecule 1 (ICAM-1), Glutathione transferase, M(TOR), Dihydrofolate reductase, Serine protease, cysteine protease, Metallo protease, and Aspartic protease.
Virological/Bacteriological Diseases (Human Rhinovirus, Influenza, SARS, MERS, Ebola, Dengue, Malaria, MRSA, Staph, e. coli, HIV)
TARGET ENZYMES: Reverse transcriptase, RNA Polymerase (all), Helicase, Topoisomerase, Integrase, Protease (viral budding), Caspase (especially caspase 8), Allantoinase, Dihydroorotase, Butyryl Cholinesterase, and Acetyl Cholinesterase.
Specific Example of One Disease: Diabetes
Type 1 Diabetes (formerly known as Juvenile Diabetes) is characterized by an inability of the body to produce or release insulin. Type 2 Diabetes (also known as Adult Onset Diabetes) is characterized by the body's inability to respond to insulin, or being insulin resistant. Both result in hyperglycemia, often followed by complications such as cardiovascular disease, retinopathy, neuropathy, and nephropathy. Type 1 Diabetes requires the administration of exogenous insulin. Type 2 Diabetes can often be initially controlled by diet alone, but usually requires treatment with antihyperglycemic agents. The most widely prescribed drug for the control of Type 2 Diabetes is the hydrochloride salt of metformin, a biguanide. Such compounds work by inhibiting liver glucose output (gluconeogenesis) and increasing the uptake of glucose by peripheral tissue (such as muscle) by stimulating glucose transporter 4 (GLUT4). A list of drugs and their mode of action is shown in Table 1.
TABLE 1CLASSMODEAGENTsulfonylureasstimulate insulin release throughtolbutamideactivation of Ca & K channelsacetohexamidetolazamidechlorpropamideglipizideglyburideglimepiridegliclazidemeglitinidesstimulate insulin release throughrepaglinideactivation of Ca & K channelsnateglinidebiguanidesinhibit gluconeogenesis, stimulatemetforminGLUT4phenforminbuforminthiazolidinedionesbind to PPARs, regulating adipocyterosiglitazonedifferentiation, FA & glucose uptake.pioglitazonetroglitazoneα-glucosidaseinhibit conversion of starch tomiglitolinhibitorglucoseacarboseGLP analogues/bind to GLP receptor, causing insulinexenatideagonistsreleaseliraglutidetaspoglutideDPP-4 inhibitorsinhibit degradation of GLP, indirectlyvildagliptincausing insulin releasesitagliptinsaxagliptinamylin analoguesinhibits gluconeogenesis, gastricpramlintideenzymes, & gastric emptying
The leading cause of non-compliance associated with the most widely prescribed antidiabetic drugs is gastro-intestinal discomfort. In particular, α-glucosidase inhibitors and amylin analogues work by slowing or inhibiting the conversion of complex carbohydrates and fats into readily absorbable simpler molecules. This leaves an environment rich in carbohydrates and lipids, readily available to intestinal micro flora. The result is often diarrhea, flatulence, inflammation, and deterioration of the intestinal lining.
Flavonoids have the basic structure:
and are classified according to IUPC (International Union of Pure and Applied Chemistry) as flavonoids (examples include quercetin and rutin), isoflavonoids (examples include daidzein and genistein), or neoflavonoids (examples include dalbergin and neoflavan).
Flavonoids are effective enzymatic inhibitors or stimulators according to the 1) number of hydroxyl units borne on their phenolic rings, 2) planarity of the molecule, and 3) position of the units on the rings. Planarity and position dictate docking potential. In general, the more hydroxyl units, the more reactive the compound is. At the same time, an increase in reactivity denotes a decrease in stability. The greater the number of hydroxyl units, the more immediate the effect. Fewer units lead to delayed effects. A formulation of flavonoids each with varying numbers of hydroxyl units may be employed as a method to elicit multiple effects. This would be accomplished by alternating ratios of different flavonoids with different numbers and hydroxyl unit orientations.
Scientific literature is replete with the effect of flavonoids on lowering blood glucose via inhibition of α-glucosidase, inhibition of glucose transporter 2 (glucose transport from the gut to the bloodstream), stimulation of glucose transporter 4 (glucose transport from the bloodstream to muscle tissue), stimulation of insulin release, inhibition of gluconeogenesis, inhibition of adipocyte growth and development, stimulation of lipolysis, inhibition of fatty acid synthesis, and increased insulin sensitivity. Flavonoids have been reported to inhibit the activity of helicobacter pylori, a major contributor to gastro-intestinal distress, as well as several other flora of the gastro-intestinal tract. In addition, flavonoids show anti-inflammatory activity and support healing of the intestinal lining.